Phase II Randomized Double‑Blind Dose‑Ranging Study of Inhaled Glycopyrronium Bromide Add‑On to Budesonide/Formoterol in Children 4–<12 years with Asthma

Trial ID: 2025-524914-26-00
Protocol: D5982C00015
Sponsor: AstraZeneca AB

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Diseases & Conditions

Asthma

Objectives

The primary objective is to assess the effect of two inhaled glycopyrronium bromide doses, added to budesonide/formoterol, on lung function in participants aged 4 to <12 years with asthma, compared with placebo.

Secondary objectives include evaluation of the same dose‑response relationship on lung function when glycopyrronium is used as add‑on therapy to budesonide/formoterol, relative to placebo.

Participants

The trial enrolled 139 participants who were children aged 4 to less than 12 years at the time of consent, encompassing both female and male subjects. All participants had a documented physician‑diagnosed asthma for at least 12 weeks prior to screening and were receiving a stable dose of inhaled corticosteroid (160–400 µg/day budesonide or equivalent) together with an additional controller medication for a minimum of 12 weeks. Eligibility required a pre‑bronchodilator FEV₁ ≤ 95 % of predicted, a Childhood Asthma Control Test score of 19 or higher at screening and randomization, a body‑mass index at or below the 95th percentile for age, and a body weight of at least 14 kg. Female participants who had experienced menarche needed a negative urine pregnancy test and appropriate contraception. Inclusion also mandated acceptable metered‑dose inhaler technique with a spacer, willingness of parents or legal guardians to adjust therapy and assist with study procedures, and provision of assent by the child when applicable. Selection was performed by confirming these criteria through medical records, spirometry, and investigator assessment; participants failing to meet spirometry quality standards or exhibiting FEV₁ < 50 % of predicted could be excluded for safety considerations. No specific dietary or physical‑activity restrictions were stipulated beyond standard care requirements.

Plans and Procedures

A Phase II, randomized, double-blind, three‑period cross‑over study will evaluate two dose levels of inhaled glycopyrronium bromide as add‑on therapy to a fixed‑dose budesonide/formoterol (BFF) metered‑dose inhaler in children aged 4 to <12 years with physician‑diagnosed asthma. After an initial screening visit to confirm eligibility, including spirometry (pre‑bronchodilator FEV1 ≤ 95 % predicted) and asthma control assessment, participants will enter a run‑in phase on BFF BID, then be randomized to receive, in a sequence of three 3‑week treatment periods separated by washout intervals, either low‑dose glycopyrronium, high‑dose glycopyrronium, or matching placebo MDI, each administered twice daily via spacer. Study visits will occur at the start of each period for dosing, safety assessment, and spirometry, with a final end‑of‑study visit after the third period to capture the primary endpoint (change from baseline in FEV1 at 1 hour post‑dose) and secondary trough FEV1 measures. The total participant involvement is approximately 10–12 weeks, including screening and follow‑up. Early termination may occur if unacceptable spirometry quality persists, FEV1 falls below 50 % of predicted, adverse events warrant discontinuation, or protocol non‑compliance is identified.

Treatment

The experimental medication glycopyrronium bromide is supplied as a pressurised inhalation suspension for inhalation use. It is provided in metered‑dose inhaler (MDI) form and administered according to the randomised dosing schedule defined in the protocol, serving as an add‑on to background therapy.

The background standard‑of‑care therapy consists of a combination inhaler containing formoterol fumarate and budesonide (BFF). This product is also a pressurised inhalation suspension intended for inhalation use and is administered throughout the study as the background regimen.

The placebo comparator is a matched MDI containing no active pharmaceutical ingredient. It is identical in appearance to the active inhalers and is used to maintain blinding across treatment periods.

All inhaled products are delivered via the same inhalation device. Administration follows the cross‑over schedule, with each treatment period separated by a wash‑out interval as specified in the study protocol. Compliance is assessed by dose‑counter readings on the inhaler devices and by participant‑maintained dosing diaries.

Efficacy

The primary efficacy endpoint is the change from baseline in FEV1 measured 1 hour after dosing at the end of treatment (3 weeks). The secondary endpoint is the change from baseline in morning pre‑dose trough FEV1 assessed at the same end‑of‑treatment time point.

Efficacy assessments will be performed at baseline and at week 3. Spirometric measurements will be obtained using standardized procedures, and values will be compared to baseline to calculate the change for each participant. Data will be analyzed according to the predefined statistical plan for the crossover design, with each dose of glycopyrronium compared to placebo.

Inclusion and Exclusion Criteria

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Inclusion Criteria

[01] Participants must be 4 to less than 12 years (has not reached his/her twelfth birthday by the time of signing informed consent/assent).
[02] Participants who have a documented history of physician-diagnosed asthma at least 12 weeks prior to Visit 1, according to the latest GINA guidelines. Healthcare records ≥ 12 weeks prior to Visit 1 must be provided to ensure consistent evaluation and follow up of treatment in those participants.
[03] Participants who have been using a stable and regular ICS (160 to 400 μg/day budesonide or equivalent dose, see Appendix E) plus one additional asthma controller medication for at least 12 weeks with stable dose ≥ 1 month prior to Visit 1.
[04] Participants must have a Childhood Asthma Control Test score ≥ 19 at Visit 1 and Visit 2.
[05] Participants must have a pre-bronchodilator FEV1 ≤ 95% of predicted normal value at Screening Visit (Visit 1), and at Randomization visit (Visit 2). Note: If participants did not withhold asthma medication(s) according to the protocol-defined washout periods, the visit should be rescheduled within the next 5 days to perform spirometry. It would be up to investigator’s judgment whether participants showing FEV1 < 50% should be excluded due to safety concerns. Participants who failed spirometry testing at any visit due to quality or FEV1 being out of range may return to the clinic to repeat spirometry testing within 5 days. If repeat spirometry fails, then participants must be screen failed. If the Principal Investigator determines the quality of the spirometry at Visit 2 is unacceptable, the site must repeat the spirometry assessment within 5 days of Visit 2, prior to randomizing the participant.
[06] BMI ≤ 95 percentile for age and body weight of ≥ 14 kg or higher.
[07] Female participants who experience menarche must have a negative urine pregnancy test from Screening (Visit 1). Post-menarchal female participants must be informed of the need to prevent pregnancy during the study using effective contraceptive methods including total sexual abstinence, barrier method or hormonal contraception that can achieve a failure rate of less than 1% per year when used consistently and correctly.
[08] Participants provided assent to join the study, as applicable. The participant’s parent(s) or the LAR will sign the ICF. The LAR has to be 18 years or older. The parents/LAR must be capable of giving signed informed consent as described in Appendix A which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
[09] Parents/LAR must be willing and able to assist the child with the procedures outlined in the protocol, e.g., compliance with study medication.
[10] Parents/legal guardian willing and, in the opinion of the investigator, able to adjust current asthma therapy, as required by the protocol.
[11] Demonstrate acceptable MDI administration technique with spacer as judged by the investigator.
[12] Received no asthma medication other than run-in BFF MDI BID and albuterol/salbutamol as needed between Visits 1 and 2, except for allowed medications defined in the CSP.

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Exclusion Criteria

[01] Life-threatening asthma defined as a history of significant asthma episode(s) requiring intubation associated with hypercapnia, respiratory arrest, hypoxic seizures, or asthma related syncopal episode(s) within the 12 months prior to Screening (Visit 1).
[02] Historical or current evidence of a clinically significant disease including, but not limited to cardiovascular, hepatic, renal, hematological, neurological, endocrine, gastrointestinal, or pulmonary (e.g., active tuberculosis, bronchiectasis, pulmonary eosinophilic syndromes). Significant is defined as any disease that, in the opinion of the investigator, would put the safety of the participant at risk through participation, or that could affect the efficacy or safety analysis if the disease/condition exacerbated during the study.
[03] Any clinically relevant abnormal findings in physical examination, clinical chemistry, hematology, vital signs, or ECG, which in the opinion of the investigator, may put the participant at risk because of his/her participation in the study, or that could affect the efficacy or safety analysis if the disease/condition exacerbated during the study. Note: Exclude participants with QTcF interval > 450 msec and participants with high degree atrioventricular block II or III, or with sinus node dysfunction with clinically significant pauses who do not have a pacemaker.
[04] Hospitalization for asthma within 8 weeks of Screening (Visit 1).
[05] Narrow-angle glaucoma not adequately treated and/or change in vision, bladder dysfunction, bladder outlet obstruction/urinary retention or any other conditions where anticholinergic treatment is contraindicated and may be relevant, in the opinion of the investigator, within 3 months of Screening (Visit 1).
[06] Use of LAMA, either alone or as part of an inhaled combination therapy, in the 12 weeks prior to Screening (Visit 1).
[07] Current use of any systemic beta-blockers. Note: All medications approved for control of intraocular pressures are allowed, including topical ophthalmic non-selective beta-blockers.
[08] Respiratory infection involving antibiotic treatment within 4 weeks prior to Screening (Visit 1) and during Screening/Run-in.
[09] Systemic corticosteroid use for any reason (including asthma exacerbations) within 4 weeks and intramuscular and depo injections within 12 weeks of Screening (Visit 1) and during Screening/Run-in.
[10] Participants with a known hypersensitivity to beta 2-agonists, corticosteroids, anticholinergics, or any component of the MDI.
[11] Participants who are medically unable to withhold their short-acting bronchodilators and other asthma medications for the 6-hour period required prior to spirometry testing at each study visit.
[12] Any marketed (e.g., omalizumab, mepolizumab, benralizumab, reslizumab) or investigational biologic within 3 months or 5 half-lives of Screening (Visit 1), whichever is longer and must not be used during study duration.
[13] Regular use of a nebulizer or a home nebulizer for receiving asthma medications.
[14] Use of any immunomodulators or immunosuppressive medication within 3 months or 5 half-lives prior to Screening (Visit 1), whichever is longer, and must not be used during study duration, except for corticosteroids for asthma exacerbation management. Note: Topical administration of immunosuppressive medication may be allowed at the discretion of the investigator.
[15] Unable to abstain from protocol-defined prohibited medications prior to and during Screening and treatment periods.
[16] Treatment with investigational study drug or participation in another clinical trial or study within the last 30 days or 5 half-lives prior to Screening (Visit 1), whichever is longer.
[17] Participants with an eGFR ≤ 60 mL/minute/1.73 m2 using the Schwartz formula prior to Visit 2.
[18] Planned hospitalization during the study.
[19] Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
[20] Judgment by the investigator that the participant should not participate in the study if the participant and/or the parent/guardian is unlikely to comply with study procedures, restrictions, and requirements.
[21] Previous enrollment in the present study.